Penetration enhancers for transdermal delivery of systemic agents

Abstract

This invention relates to a method for administering systemically active agents including therapeutic agents through the skin or mucosal membranes of humans and animals and into the blood stream in a transdermal device or formulation comprising topically administering with said systemic agent an effective amount of a membrane penetration enhancer being a carboxylic acid derivative or a salt thereof represented in one embodiment by the general formula ##STR1## wherein W represents oxygen, sulfur, or two hydrogen radicals; wherein Z represents oxygen, sulfur, or --CH 2 --; wherein R represents alkyl optionally substituted with one to three double or triple bonds, --SR'", --OR'", --NHR'", --CH 3 , or COOR 1 , and wherein R 1 represents hydrogen or lower alkyl; wherein R'" represents alkyl, alkylthioalkyl, alkoxyalkyl, substituted aminoalkyl, optionally substituted with a phenyl, benzoyl or heterocyclic group; wherein R' represents hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, --(CH2) y COOR 1 and with y being between zero and 3, inclusive; and wherein R" represents hydrogen or --(CH2) y COOR 1 such that when R" is hydrogen, then W is two hydrogen radicals and R' is not hydrogen; and when R' is hydrogen, then R" is not hydrogen; and wherein m is between one and 5, preferably 2, 3, or 4, while n is between 1 and 24, preferably between 5 and 12, and x is zero or 1, inclusive. It has been found that both open and closed-chain embodiments of the penetration enhancer are sufficient to carry physiologically active agents through body membranes and into the bloodstream.

Having now described the invention, we claim: 
     
       1. A method for topically administering systemically active agents through the skin or mucosal membranes of humans and animals, which method comprises the topical administration of effective amounts of a systemically active agent and a membrane penetration enhancer having the structural formula: ##STR8## wherein A represents --(CH 2 )--; R represents COOR 1 , where R 1  represents a hydrogen or lower alkyl radical; R 2  and R 3  each independently represent alkyl optionally substituted with 1 to 3 double or triple bonds or CH 3  ;   m represents 0 to 5;   n represents 1 to 24;   R' represents hydrogen, alkoxy, acyloxy, alkythio, and hydroxy;   R" represents hydrogen or (CH 2 ) y  COOR 1  where y represents 0 to 3 inclusive.   
     
     
       2. The method of claim 1 wherein m is 1 or 2. 
     
     
       3. The method of claim 1 wherein n is between 5 and 12. 
     
     
       4. The method of claim 1 wherein the systemically active agent is a therapeutic agent. 
     
     
       5. The method of claim 1 wherein the administration is concurrent.